Combination of brimonidine and timolol for topical ophthalmic use

ABSTRACT

Disclosed are pharmaceutical compositions comprising brimondine and timolol for topical ophthalmic delivery and a method of treatment comprising administering said composition when indicated for glaucoma and associated conditions such as elevated intraocular pressure in the eyes of humans.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is continuing application of patent applicationSer. No. 11/946,828, filed Nov. 28, 2007 which is a continuation ofpatent application Ser. No. 10/685,941, filed Oct. 14, 2003, which is acontinuing application of patent application Ser. No. 10/126,790, filedon Apr. 19, 2002.

BACKGROUND

This invention relates to the topical ophthalmic use of brimonidine incombination with timolol when indicated for treatment of glaucoma orocular hypertension. Such combinations or formulations are available forseparate use in the ophthalmic art and have been combined in serialapplication during the course of treatment of glaucoma. However, thereare concerns and expressed reservations in the ophthalmic communityabout patient compliance when the patient is required to administerseparate medications to treat a single disease or condition such asglaucoma. There is, moreover, a long felt need for an effective and safetopical ophthalmic pharmaceutical composition including brimonidine andtimolol which has increased stability and requires a lower effectiveconcentration of preservative as compared to the individual agents takenalone. Finally, there is a need to increase the efficacy of many topicalophthalmic agents, without increasing the systemic concentration of suchtopical agents, since it is well known that many of suchtopically-applied ophthalmic agents cause systemic side effects, e.g.drowsiness, heart effects, etc. Unexpectedly it has been discovered thatbrimonidine in combination with timolol meets these criteria.

Brimonidine is disclosed in U.S. Pat. No. 3,890,319. The use ofbrimonidine for providing neuroprotection to the eye is disclosed inU.S. Pat. Nos. 5,856,329; 6,194,415 and 6,248,741.

Timolol, as an ophthalmic drug, is disclosed in U.S. Pat. Nos. 4,195,085and 4,861,760.

DESCRIPTION OF THE INVENTION

Brimonidine is an alpha adrenergic agonist represented by the followingformula:

The chemical name for brimonidine is5-Bromo-6-(2-imidazolidinylideneamino)quinoxaline L-tartrate.

Timolol is a beta adrenergic agent represented by the following formula:

Brimonidine is available from Allergan, Inc., Irvine, Calif. as anophthalmic pharmaceutical product having the name Alphagan®.

Timolol is available from various sources, including Merck Co., Rahway,N.J.

The compositions of the present invention are administered topically.The dosage is 0.001 to 1.0, e.g. mg/per eye BID; wherein the cited massfigures represent the sum of the two components, brimonidine andtimolol. The compositions of the present invention can be administeredas solutions in a suitable ophthalmic vehicle.

In forming compositions for topical administration, the mixtures arepreferably formulated as 0.01 to 0.5 percent by weight brimonidine and0.1 to 1.0 percent by weight timolol solution in water at a pH of 4.5 to8.0, e.g. about 6.9. While the precise regimen is left to the discretionof the clinician, it is recommended that the solution be topicallyapplied by placing one drop in each eye two times a day. Otheringredients which may be desirable to use in the ophthalmic preparationsof the present invention include preservatives, co-solvents andviscosity building agents.

Antimicrobial Preservative:

Ophthalmic products are typically packaged in multidose form.Preservatives are thus required to prevent microbial contaminationduring use. Suitable preservatives include: benzalkonium chloride,thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethylalcohol, edetate disodium, sorbic acid, Onamer M, or other agents knownto those skilled in the art. In the prior art ophthalmic products,typically such preservatives are employed at a level of from 0.004% to0.02%. In the compositions of the present application the preservative,preferably benzalkonium chloride, may be employed at a level of from0.001% to less than 0.01%, e.g. from 0.001% to 0.008%, preferably about0.005% by weight. It has been found that a concentration of benzalkoniumchloride of 0.005% is sufficient to preserve the compositions of thepresent invention from microbial attack. This concentration may beadvantageously compared to the requirement of 0.01% benzalkoniumchloride to preserve timolol in the individual, commercially-availableophthalmic products. Moreover, it has been found that adequate loweringof intraocular pressure has been obtained when administering thecompositions of this invention twice a day as compared to theFDA-approved regimen wherein brimonidine ophthalmic solution, i.e.Alphagan® ophthalmic solution is administered three times a day andtimolol ophthalmic solution, i.e. Timoptic® ophthalmic solution isadministered twice a day. This results in the exposure of the patient to67% and 50% of benzalkonium chloride, with the compositions of thisinvention, as compared to the administration of Alphagan® and Timoptic®,respectively. In FDA-approved adjunctive therapy, wherein Alphagan® andTimoptic® are serially administered, the patient is exposed to almostthree times the concentration of benzalkonium chloride as compared tothe administration of the compositions of this invention twice a day.(It is noted that it is known that benzalkonium chloride at highconcentrations is cytotoxic. Therefore, minimizing the patient'sexposure to benzalkonium chloride, while providing the preservativeeffects afforded by benzalkonium chloride, is clearly desirable.)

Co-Solvents:

The solubility of the components of the present compositions may beenhanced by a surfactant or other appropriate co-solvent in thecomposition. Such cosolvents include polysorbate 20, 60, and 80,Pluronic F68, F-84 and P-103, cyclodextrin, or other agents known tothose skilled in the art. Typically such co-solvents are employed at alevel of from 0.01% to 2% by weight.

Viscosity Agents:

Viscosity increased above that of simple aqueous solutions may bedesirable to increase ocular absorption of the active compound, todecrease variability in dispensing the formulation, to decrease physicalseparation of components of a suspension or emulsion of the formulationand/or to otherwise improve the ophthalmic formulation. Such viscositybuilding agents include as examples polyvinyl alcohol, polyvinylpyrrolidone, methyl cellulose, hydroxy propyl methylcellulose,hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propylcellulose or other agents known to those skilled in the art. Such agentsare typically employed at a level of from 0.01% to 2% by weight.

The present invention further comprises an article of manufacturecomprising packaging material and a pharmaceutical agent containedwithin said packaging material, wherein the pharmaceutical agent istherapeutically effective for lowering intraocular pressure and whereinthe packaging material comprises a label which indicates thepharmaceutical agent can be used for lowering intraocular pressure andwherein said pharmaceutical agent comprises an effective amount of

brimonidine and an effective amount of timolol.

The following example is a representative pharmaceutical composition ofthe invention for topical use when indicated for treating glaucoma.

Example I

The combination of active pharmaceutical ingredients is as follows:

Brimonidine Tartrate 0.20% (w/v) and Timolol Maleate 0.68% (w/v)(Equivalent to 0.50% (w/v) timolol)

The Brimonidine-Timolol combination formulation presented in the Table,below, is a sterile, preserved, aqueous solution. The formulationvehicle is based upon a timolol ophthalmic solution which contains anisotonic phosphate buffer system at pH 6.9. The formulation preservativeis benzalalkonium chloride (BAK) at a concentration of 0.005% (w/v) (50ppm). The formulation passes regulatory required preservative efficacytesting (PET) criteria for USP (United States Pharmacopoeia) and EP(European Pharmacopoeia-A and -B over 24 months.

TABLE Ingredient Function Concentration, %(w/v) Brimonidine TartrateActive 0.2 Timolol Maleate, EP Active 0.68¹ Benzalkonium Chloride, NF,EP Preservative 0.005 Sodium Phosphate, Buffer 0.43 monobasicmonohydrate, USP Sodium Phosphate, Buffer 2.15 dibasic heptahydrate, USPSodium Hydroxide, NF pH adjust Adjust pH to 6.9 Hydrochloric Acid, NF pHadjust Adjust pH to 6.9 Purified Water, USP, EP Solvent q.s. ad¹Equivalent to 0.5%(w/v) Timolol, free base

The pharmaceutical composition of Example I is used in the clinicalstudy reported below.

Example II Objectives

To compare the safety and efficacy of twice-daily dosed brimonidinetartrate 0.2%/timolol 0.5% ophthalmic solution combination (henceforthreferred to as Combination) with that of twice-daily dosed timololophthalmic solution 0.5% (henceforth referred to as Timolol) andthree-times-daily dosed ALPHAGAN® (brimonidine tartrate ophthalmicsolution) 0.2% (henceforth referred to as Brimonidine) administered forthree months (plus 9-month masked extension) in patients with glaucomaor ocular hypertension.

Methodology:

Structure: multicenter, double-masked, randomized, parallel-group,active controlRandomization: patients were randomized to one of the 3 masked treatmentgroups (Combination, Brimonidine or Timolol) based on an even allocationat each siteVisit Schedule: prestudy, baseline (day 0), week 2, week 6, month 3,month 6, month 9, and month 12

Number of Patients (Planned and Analyzed):

560 planned to enroll; 586 enrolled (Combination=193, Brimonidine=196,Timolol=197); 502 completed. Mean (range) age: 62.4 (23 to 87) years;46.1% (270/586) males, 53.9% (316/586) females.

Diagnosis and Main Criteria for Inclusion:

Diagnosis: ocular hypertension, chronic open-angle glaucoma, chronicangle-closure glaucoma with patent iridotomy, pseudoexfoliative glaucomaor pigmentary glaucoma and requiring bilateral treatment.Key Inclusion Criteria: ≧18 years, day 0 (post-washout) intraocularpressure (IOP)≧22 mm Hg and ≧34 mm Hg in each eye and asymmetry of IOP≧5 mm Hg, best-corrected Early Treatment of Diabetic Retinopathy Study(ETDRS) visual acuity equivalent to a Snellen score of 20/100 or betterin each eye.Key Exclusion Criteria: uncontrolled systemic disease, abnormally low orhigh blood pressure or pulse rate for age or contraindication tobeta-adrenoceptor antagonist therapy, anticipated alteration of existingchronic therapy with agents which could have a substantial effect onIOP, contraindication to brimonidine therapy, allergy or sensitivity toany of the study medication ingredients, anticipated wearing of contactlenses during the study, laser surgery, intraocular filtering surgery orany other ocular surgery within the past 3 months, or required chronicuse of other ocular medications during the study (intermittent use ofartificial tear product was allowed).

Test Product, Dose and Mode of Administration, Batch Number:

Brimonidine tartrate 0.2%/timolol 0.5% combination ophthalmic solutionone drop (−35 μL) instilled in each eye BID in the morning and evening;and vehicle of the Combination ophthalmic solution, one drop (−35 μL)instilled in each eye once daily (QD) in the afternoon (for maskingpurposes).Duration of Treatment: 3 months (with a 9-month masked extension)

Reference Therapy, Dose and Mode of Administration, Batch Number:

Active control ALPHAGAN® (brimonidine tartrate ophthalmic solution)0.2%, one drop (˜35 μL) instilled in each eye TID in the morning,afternoon, and evening.Active control timolol ophthalmic solution 0.5%, one drop (˜35 μL)instilled in each eye BID in the morning and evening; and vehicle of theCombination ophthalmic solution, one drop (˜35 μL) instilled in each eyeonce daily (QD) in the afternoon (for masking purposes).

Criteria for Evaluation: Efficacy:

IOP (hours 0, 2, 7, and 9), patient satisfaction questionnaire, patientcomfort of study medication questionnaire, pharmacoeconomic evaluationby investigator

Safety:

Adverse events (AE), biomicroscopy, visual acuity (VA), visual field,ophthalmoscopy, cup/disc ratio, heart rate, blood pressure, hematology,serum chemistry, urinalysis and pregnancy test.

Other:

Quantitation of plasma brimonidine and timolol concentrations (atselected sites), resource utilization (to be reported upon completion ofthe 1 year study).

Statistical Methods:

All data were summarized with descriptive statistics, frequency tables,and/or data listings. Safety analyses included all patients who receivedat least 1 dose of study medication. Analyses were performed for theprimary efficacy variable IOP using the intent-to-treat (ITT) populationwith last observation carried forward (LOCF), and the per protocolpopulation with observed cases.Ordinal categorical variables were analyzed by the Wilcoxon rank-sumtest. Nominal categorical variables were analyzed using Fisher's exactor Pearson's chi-square tests. Within-group changes from baseline forcategorical variables were analyzed using the Wilcoxon signed-rank test.Continuous variables (eg, IOP) were analyzed using analysis of variance(ANOVA). Within-group changes from baseline for continuous variableswere analyzed using paired t-tests.A 2-way ANOVA model with factors for treatment and investigator was usedfor the analysis of IOP. Comparisons were made between the Combinationand each of the 2 monotherapies in a pairwise fashion using contrastsfrom the ANOVA model, with the same error term. A separate ANOVA modelwas employed at each hour/visit measurement of IOP. Each of the 2 nullhypotheses (Combination versus Timolol and Combination versusBrimonidine) was tested at the 0.05 significance level. Point estimatesof the mean treatment differences, as well as 2-sided 95% confidenceintervals (CI) of the difference, were provided at each timepoint.

Summary—Conclusions: Efficacy:

At baseline, mean values of diurnal IOP ranged from 22.2 mm Hg to 24.9mm Hg in the Combination group, 22.5 mm Hg to 25.0 mm Hg in theBrimonidine group, and 22.3 mm Hg to 24.8 mm Hg in the Timolol group.There were no statistically significant differences between treatmentgroups.Mean changes from baseline diurnal IOP at week 2, week 6 and month 3ranged from:

−5.2 to −7.9 mm Hg in the Combination group

−3.5 to −5.7 mm Hg in the Brimonidine group

−4.5 to −6.4 mm Hg in the Timolol group

The mean decreases from baseline diurnal IOP were statisticallysignificant within each treatment group at each follow-up timepoint(p<0.001).The mean decrease from baseline diurnal IOP was statisticallysignificantly greater with Combination than with Brimonidine at hours 0,2, and 7 at all follow-up visits (p<0.001). In addition, clinicallysignificant differences of more than 1.5 mm Hg in mean change frombaseline IOP favoring Combination over Brimonidine were seen at hours 0,2, and 7 at all follow-up visits. At hour 9, the decreases from baselinediurnal IOP were greater for the Combination group than the Brimonidinegroup at all follow-up visits, although the differences were notstatistically significant (p≧0.104).The mean decrease from baseline diurnal IOP was statisticallysignificantly greater with Combination than with Timolol at hours 0, 2,7 and 9 at all follow-up visits (p 0.041). In addition, clinicallysignificant differences of more than 1.5 mm Hg in mean change frombaseline IOP favoring Combination over Timolol were seen at week 2(hours 0, 2, and 7), week 6 (hours 2 and 7), and month 3 (hours 0 and2).Mean values of diurnal IOP at week 2, week 6 and month 3 ranged from:

15.9 to 18.1 mm Hg in the Combination group

17.4 to 21.5 mm Hg in the Brimonidine group

17.5 to 18.9 mm Hg in the Timolol group

Mean values of diurnal IOP were statistically significantly less withCombination than with Brimonidine at hours 0, 2, and 7 at all follow-upvisits (p<0.001) and at hour 9 at week 6 and month 3 (p 0.011). The meanvalues of IOP at hour 9 at week 2 were lower for the Combination groupthan the Brimonidine group, although the difference was notstatistically significant (p=0.205). In addition, clinically significantdifferences of more than 1.5 mm Hg in mean IOP favoring Combination overBrimonidine were seen at hours 0, 2, and 7 at all follow-up visits andat hour 9 at month 3.Mean values of diurnal IOP were statistically significantly less withCombination than with Timolol at hour 0 at week 2 and month 3; and athours 2, 7 and 9 at all follow-up visits (p 0.050). The mean values ofIOP at hour 0, week 6, were lower for the Combination group than theTimolol group, although the difference was not statistically significant(p=0.102). In addition, clinically significant differences of more than1.5 mm Hg in mean IOP favoring Combination over Timolol were seen atweek 2 (hours 0, 2, and 7), week 6 (hours 2, 7, and 9), and month 3(hours 2 and 9).At the month 3 or exit visit, a statistically significantly greater“yes” response to the Investigator Pharmacoeconomic Evaluation wasrecorded for patients receiving Combination (91.1%, 173/190) than forpatients receiving Brimonidine (73.4%, 141/192, p<0.001). A “yes”response was recorded for 92.7% (179/193) of patients receiving Timolol.There were no statistically significant differences in the change frombaseline in treatment comfort between Combination and each of themonotherapy groups.Treatment satisfaction was better than baseline for a statisticallysignificantly greater percentage of patients in the Combination group(23.4%, 36/154) than in the Brimonidine group (13.2%, 20/151, p=0.005).A total of 19.9% (30/151) of patients in the Timolol group reportedbetter treatment satisfaction than baseline.

Safety:

Through month 3 of the study, 53.4% (103/193) of patients in theCombination group, 61.7% (121/196) of the Brimonidine group, and 50.8%(100/197) of the Timolol group experienced one or more adverse events,regardless of causality. The incidences of oral dryness, eye pruritus,foreign body sensation and conjunctival folliculosis were statisticallysignificantly lower with the Combination than with Brimonidine(p≦0.034), while burning and stinging were statistically significantlyhigher with the Combination than with Brimonidine (p≦0.028). There wereno statistically significant differences in adverse events between theCombination and Timolol, except for a statistically significantly higherincidence of eye discharge with the Combination (2.6%, 5/193) comparedto Timolol (0%, 0/197; p=0.029). The most frequently reported adverseevents (>3% in any treatment group) were as follows, tabulated bydescending order in the Combination group:

Combination Brimonidine Timolol Preferred Term N = 193 N = 196 N = 197burning sensation in eye 23 (11.9%) 11 (5.6%) 25 (12.7%) conjunctivalhyperemia 16 (8.3%)  23 (11.7%) 11 (5.6%)  stinging sensation eye 13(6.7%)  4 (2.0%) 11 (5.6%)  infection (body as a 11 (5.7%)  6 (3.1%) 8(4.1%) whole) visual disturbance 6 (3.1%) 11 (5.6%) 3 (1.5%) epiphora 5(2.6%) 8 (4.1%) 3 (1.5%) oral dryness 4 (2.1%) 19 (9.7%) 1 (0.5%) eyepruritus 3 (1.6%) 13 (6.6%) 3 (1.5%) allergic conjunctivitis 3 (1.6%) 7(3.6%) 0 (0.0%) asthenia 3 (1.6%) 6 (3.1%) 1 (0.5%) foreign bodysensation 2 (1.0%) 10 (5.1%) 5 (2.5%) conjunctival folliculosis 2 (1.0%)9 (4.6%) 1 (0.5%) somnolence 2 (1.0%) 7 (3.6%) 0 (0.0%)Adverse events led to the discontinuation of 3.6% (7/193) of patients inthe Combination group, similar to 3.0% (6/197) of patients in theTimolol group, and statistically significantly less than 14.3% (28/196)of patients in the Brimonidine group (p<0.001). Serious adverse eventswere reported for 1.0% (2/193) of patients in the Combination group,2.0% (4/196) of patients in the Brimonidine group, and 2.0% (4/197) ofpatients in the Timolol group. Two patients receiving Timolol had 4serious adverse events (emphysema in one patient; nausea, sweating, andtachycardia in the other patient) which were considered possibly relatedto the study drug. There was 1 death in the Brimonidine group, possiblydue to complications from cardiac surgery, and not related to studydrug.There were no clinically relevant differences between the Combinationand either of the individual components in the mean change from baselineto month 3 for any hematology, chemistry, or urinalysis parameter.Statistically significant (p≦0.048) within-group changes from baselinewere found, but were small and not clinically relevant.Small but statistically significant (p≦0.001) mean reductions in heartrate ranging from −2.1 to −3.7 bpm were seen with the Combination,similar to Timolol. Small but statistically significant (p≦0.003) meanreductions in blood pressure at hour 2 (postdose) were seen with theCombination, similar to Brimonidine. These small changes in mean heartrate and blood pressure were associated with clinical symptoms in only afew patients.Increases from baseline in the severity of conjunctival erythema andconjunctival follicles on biomicroscopy were statistically significantlyless with the Combination than with Brimonidine (p≦0.011). The majorityof patients in each treatment group showed less than a 2-line changefrom baseline visual acuity. There were no significant between-groupdifferences for changes in visual fields or cup/disc ratio.

Pharmacokinetics:

Blood samples were available for 55 patients in the Combination group,49 patients in the Brimonidine group, and 54 patients in the Timololgroup. All samples were assayed for both brimonidine (lower limit ofquantitation [LLOQ] 5 pg/mL) and timolol (LLOQ 5 pg/mL). Plasmabrimonidine and timolol concentrations were not quantifiable in all but1 sample on day 0, hour 0 for both Combination and the monotherapytreatment groups.

In the Combination group, mean±standard deviation (SD) plasmabrimonidine concentrations 1 hour postdose at week 2 and month 3 were49.7±36.1 and 52.8±46.7 pg/mL, respectively. In the Brimonidine group,mean±SD plasma brimonidine concentrations at week 2 and month 3 were81.0±63.8 and 78.6±48.9 pg/mL, respectively. In the Combination group,mean±SD plasma timolol concentrations at week 2 and month 3 were0.499±0.327 and 0.586±0.580 ng/mL, respectively. In the Timolol group,mean±SD plasma timolol concentrations at week 2 and month 3 were0.950±0.709 and 0.873±0.516 ng/mL, respectively.

Plasma brimonidine and timolol concentrations 1 hour postdose weresteady and did not increase over the 3-month study duration. Brimonidineconcentrations were 39%, 34% and 39% lower in the Combination group thanin the monotherapy group at week 2 (p=0.004), month 3 (p=0.013), andmonth 12, respectively. Timolol concentrations were 47% and 33% lower inthe Combination group than in the monotherapy group at week 2 (p<0.001)and month 3 (p=0.011), respectively.Timolol concentrations were also significantly lower in the combinationtreatment group than in the Timolol monotherapy treatment group(p=0.0006). Timolol concentrations were 49%, 32%, and 21% lower in thecombination group than in the monotherapy group at week 2, month 3, andmonth 12, respectively.The plasma brimonidine concentration in males was statisticallysignificantly lower than in females for the Brimonidine group (37% lowerat week 2 [p=0.034] and 37% lower at month 3 [p=0.017]); the differencewas not statistically significant in the Combination group. The plasmatimolol concentration in males was statistically significantly lowerthan in females for both the Combination group (not statisticallysignificant at week 2; 52% lower at month 3 [p=0.012]) and the Timololgroup (45% lower at week 2 [p=0.006] and 39% lower at month 3[p=0.003]).Plasma brimonidine concentration in the elderly group was notsignificantly different from in the young group for the combined datafrom both the combination and Brimonidine treatment groups(p-value=0.1323). However, plasma timolol concentration in the younggroup was significantly lower than in the elderly group for combineddata from both the combination and the Timolol treatment groups(p-value=0.0005).

Conclusions:

The Combination treatment (brimonidine tartrate 0.2%/timolol 0.5%)administered BID for 3 months was superior to Timolol (timolol 0.5%) BIDand Brimonidine (brimonidine tartrate 0.2%) TID in lowering the elevatedIOP of patients with glaucoma or ocular hypertension. The Combinationadministered BID demonstrated a favorable safety profile that wascomparable to Timolol BID and better than Brimonidine TID with regard tothe incidence of adverse events and discontinuations due to adverseevents.

The invention has been described herein by reference to certainpreferred embodiments. However, as obvious variations thereon willbecome apparent to those skilled in the art, the invention is not to beconsidered as limited thereto.

1. A pharmaceutical composition comprising: brimonidine at aconcentration of about 0.01% w/v to about 0.2% w/v, and timolol at aconcentration of about 0.1% w/v to about 0.5% w/v, wherein thecomposition is sterile and is suitable for topical ophthalmic use. 2.The composition of claim 1, wherein the concentration of timolol isabout 0.5% w/v.
 3. The composition of claim 1, wherein the concentrationof brimonidine is about 0.2% w/v.
 4. The composition of claim 1, furthercomprising a phosphate buffer.
 5. The composition of claim 4, furthercomprising about 0.005% benzalkonium chloride.
 6. The composition ofclaim 1, wherein the brimondine is brimonidine tartrate.
 7. Thecomposition of claim 1, wherein the brimondine is brimonidine free base.8. The composition of claim 1, wherein the timolol is timolol maleate.9. The composition of claim 1, wherein the timolol is timolol free base.10. The composition of claim 1, having a pH of about 6.9
 11. Thecomposition of claim 1, further comprising carboxymethyl cellulose at aconcentration of about 0.01% w/v to about 2% w/v.
 12. A method ofreducing intraocular pressure comprising administering a composition ofclaim 1 to an eye.
 13. The method of claim 12, wherein the compositionis administered at an interval of about 12 hours.
 14. The method ofclaim 12, wherein the method results in a lower incidence ofconjunctival hyperemia as compared to administration of brimonidine atan interval of about 8 hours without the concurrent administration oftimolol.
 15. The method of claim 12, wherein the method results in alower incidence of visual disturbance as compared to administration ofbrimonidine at an interval of about 8 hours without the concurrentadministration of timolol.
 16. The method of claim 12, wherein themethod results in a lower incidence of epiphora as compared toadministration of brimonidine at an interval of about 8 hours withoutthe concurrent administration of timolol.
 17. The method of claim 12,wherein the method results in a lower incidence of oral dryness ascompared to administration of brimonidine at an interval of about 8hours without the concurrent administration of timolol.
 18. The methodof claim 12, wherein the method results in a lower incidence of eyepruritus as compared to administration of brimonidine at an interval ofabout 8 hours without the concurrent administration of timolol.
 19. Themethod of claim 12, wherein the method results in a lower incidence ofallergic conjunctivitis as compared to administration of brimonidine atan interval of about 8 hours without the concurrent administration oftimolol.
 20. The method of claim 12, wherein the method results in alower incidence of asthenia as compared to administration of brimonidineat an interval of about 8 hours without the concurrent administration oftimolol.
 21. The method of claim 12, wherein the method results in alower incidence of foreign body sensation as compared to administrationof brimonidine at an interval of about 8 hours without the concurrentadministration of timolol.
 22. The method of claim 12, wherein themethod results in a lower incidence of conjunctival folliculosis ascompared to administration of brimonidine at an interval of about 8hours without the concurrent administration of timolol.
 23. The methodof claim 12, wherein the method results in a lower incidence ofsomnolence as compared to administration of brimonidine at an intervalof about 8 hours without the concurrent administration of timolol.